Visual Impairment, Eye Conditions, and Diagnoses of Neurodegeneration and Dementia

Key Points Question Are eye conditions and visual acuity risk factors for Alzheimer disease (AD) and related dementias? Findings In this cohort study of 304 953 UK Biobank participants, cataracts were associated with lower total gray matter volume, white matter hyperintensities, and increased risk of dementia, especially vascular dementia. Mendelian randomization analyses estimated that cataracts were associated with a 92% increase in the odds of vascular dementia risk; although poor visual acuity was associated with an increased risk of dementia, myopia was not associated with dementia in genetic analyses. Meaning These results suggest that cataracts increase the risk of dementia through vascular and non-AD mechanisms; treating or preventing cataracts may reduce dementia risk.


Findings
In this cohort study of 304 953 UK Biobank participants, cataracts were associated with lower total gray matter volume, white matter hyperintensities, and increased risk of dementia, especially vascular dementia.
Mendelian randomization analyses estimated that cataracts were associated with a 92% increase in the odds of vascular dementia risk; although poor visual acuity was associated with an increased risk of dementia, myopia was not associated with dementia in genetic analyses.
Meaning These results suggest that cataracts increase the risk of dementia through vascular and non-AD mechanisms; treating or preventing cataracts may reduce dementia risk.

Introduction
Visual impairment and ocular disease are emerging as potential modifiable risk factors for Alzheimer disease (AD) and related dementias (ADRDs). 1 Self-reported vision impairment, 2,3 eye conditions such as cataracts, 4,5 and poor visual acuity [6][7][8] are associated with an increased risk of dementia.If causal, this association would be clinically meaningful; some vision impairments can be reversed or corrected.For example, observational studies have reported that cataract surgery is associated with a decreased risk of dementia. 4,9tablishing the causality of this association is methodologically difficult.Both vision impairment and ADRDs can develop slowly over decades, they share risk factors, 10,11 and early ADRDs could affect visual processing (reverse causation). 12Additionally, previous studies are observational and may be affected by unmeasured confounding by social or other health factors [13][14][15] or confounding by indication. 16Alternative approaches are needed to inform whether vision care could delay the onset of ADRD.
Genetic variants associated with eye conditions or AD [17][18][19] can be leveraged to estimate causal associations, because genetic variants are likely independent of key confounders.Mendelian randomization (MR) uses genetic variants, single-nucleotide variants (SNVs), as instruments, allowing for an unbiased estimate of causal effect, provided certain assumptions are met. 20,21Few studies have used MR methods to evaluate associations between vision impairments and dementia.
One study reported null findings for the association between cataracts and AD; however, this study did not examine vision impairments or dementia more broadly. 22Furthermore, previous studies have not investigated related indicators of ADRD, such as neuroimaging markers, which would provide convergent evidence and elucidate biological pathways.
We evaluated the possible associations between visual impairment, cataracts, and ADRD in the UK Biobank (UKB).With recent interest in visual acuity 23 and cataracts 9 as dementia risk factors, we focused our genetic analyses on cataracts and myopia.With MR, we first used genetic risk for AD to evaluate whether shared genetics or incipient AD increases the risk of later vision impairment or eye conditions (Figure 1A).Second, we used genetic risk for eye conditions (cataracts and myopia) to evaluate whether incipient eye conditions increase the risk of ADRD, vascular dementia (VaD), or AD (Figure 1B).Third, to explore biological pathways, we evaluated eye conditions and brain magnetic resonance imaging (MRI) outcomes.

Study Population
The UKB is an ongoing biobank study that enrolled more than 500 000 individuals aged 40 to 69 years from 2006 to 2010 across the UK. 24Participants provided blood samples, survey responses, and their electronic health records are linked for follow-up through November 2021; a subset completed visual acuity tests (calendar years 2006-2010) and brain MRI (calendar years 2014-2010).This cohort study followed the Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomization (STROBE-MR) guidelines (eAppendix 1). 25 Ethics approval for data collection was obtained from the National Health Service National Research Ethics Service, and all participants provided written informed consent.Participants receive compensation for travel.

Eye Disorders and Visual Acuity
Participants self-reported their history of eye problems (cataracts, glaucoma, age-related macular degeneration, and diabetic retinopathy) during their baseline visit.Participants also self-reported their history of cataract surgery.For analyses in which cataracts were the outcome, we used additional diagnoses of senile cataracts that were obtained from linked electronic health record data through the end of 2021.In a subset, the presence of myopia was determined from refraction error, measured by noncycloplegic autorefraction, 26,27 and visual acuity was measured in both eyes as the logMAR chart. 27The measure from the better eye was used.Binary 20/40 vision was calculated using a logMAR cutoff of 0.3.

Dementia
Incident dementia cases, including AD, VaD, and nonspecific dementia, were ascertained based on dementia diagnoses from linked primary care and inpatient electronic health records through 2021 using International Statistical Classification of Diseases and Related Health Problems, 10th Revision, codes (eTable 1 in Supplement 1). 28,29In sensitivity analyses, we restricted the outcome to dementia subtypes (AD or VaD).

Brain Volumes
We selected 5 neuroimaging regions of interest as secondary outcomes.Based on research showing their association with cognitive decline, we included measures of total brain volume, 30 total gray matter volume, 31,32 hippocampal volume (both hemispheres), 31,33 white matter hyperintensity volume, 34 and mean cortical thickness in an AD signature region. 35The AD signature region is a surface area-weighted average of cortical thicknesses across 6 regions.We also included the volume of 1 visual region (ie, lateral occipital cortex) under the hypothesis that visual impairment may cause atrophy in visual tracts and regions. 36,37gure Magnetic resonance imaging data were obtained from the first imaging visit and were acquired using identical scanners and the same protocol across sites. 38Volumetric, cortical thickness, and surface area measures were obtained using FreeSurfer.All volumetric measures were adjusted for intracranial volume.

Genetic Instruments for Cataracts, Myopia, and AD
Samples were genotyped in batches using 2 closely related arrays. 39,40We selected genetic instruments based on previously published genome-wide association studies (GWAS) for cataracts, 18 myopia, 19 and AD. 17 We created GRS based on genome-wide significant SNVs identified in each GWAS (P < 1 × 10 −8 unless otherwise specified).Genetic risk scores were calculated by multiplying each individual's risk allele count for each locus by the effect estimates for that SNV from the respective GWAS and summing scores to create a weighted sum. 41SNPs in linkage disequilibrium were removed (r 2 > 0.3).A primary GRS for cataracts (cataracts-GRS) was calculated from 43 SNVs from a 23andMe replication GWAS (347 209 cases and 2 887 246 controls) on cataracts (eTable 2 in Supplement 1). 18We examined a secondary GRS for cataracts based on variants independent from those identified in the UKB to minimize any weak instrument bias. 42The secondary cataract-GRS was based on 7 SNVs (P < 1 × 10 −7 ) identified from participants with European ancestry from the Genetic Epidemiology Research in Adult Health and Aging (GERA) study (28 092 cases and 50 487 controls).
Final GRS were transformed into a z score.The primary GRS for myopia (myopia-GRS) was limited to 55 SNVs that replicated in 23andMe and were statistically significant (P < 1 × 10 −8 ) from the 23andMe replication study (eTable 3 in Supplement 1).Secondary analyses used a myopia-GRS (106 SNVs) created from the study's GERA subcohort.In addition, a GRS for AD (AD-GRS) was created using effect estimates from a large GWAS on dementia that did not include the UKB. 17We focused on genetic risk for AD since genetic risk for AD is well described.The final AD-GRS was a weighted sum of 27 SNVs, including 2 apolipoprotein E (APOE) ε4 alleles (eTable 4 in Supplement 1).We replicated our analyses using a version of the AD-GRS without the APOE alleles.

Covariates
Age at visit (baseline or imaging), self-reported sex (male and female), self-reported racial and ethnic identity (Asian, Black, Chinese, White, multiple races, and other), quintiles of index of multiple deprivation by country of origin (highest, above average, average, below average, and lowest), and 6 indicators for a history of relevant comorbidities (falls, broken bones, cardiovascular disease, stroke, diabetes, and problems hearing) were reported at baseline.We adjusted for racial and ethnic identity because there are racial disparities in visual impairment and dementia that we do not believe are explained by other covariates included in UKB data. 60,61Genetic models (including GRS and MR models) were adjusted for age, sex, and the first 10 principal components to adjust for confounding by population stratification.Imaging models included adjustment for imaging center.Models including visual acuity and myopia were additionally adjusted for use of corrective lenses.

Statistical Analysis Observational Analyses
We assessed the association between eye problems (cataracts, myopia, binary 20/40 vision, glaucoma, diabetic retinopathy, and age-related macular degeneration) and all-cause dementia, AD, and VaD using Cox proportional hazards regression models censored for death, loss to follow-up, or end of study period.In a secondary model focused on cataracts, we evaluated whether a history of cataract surgery modified associations with dementia risk.We also investigated cross-sectional differences in imaging markers using linear regressions.

Mendelian Randomization
To better investigate possible causality, we used genetic risk to evaluate the associations between cataracts, myopia, and dementia.There are 4 main assumptions that need to be met for MR. 43 the relevance condition requires that SNVs are associated with the risk factor or exposure (eg, SNVs in the AD-GRS must be associated with AD).We confirmed that each GRS (cataracts-GRS, myopia-GRS, and AD-GRS) was associated with its corresponding exposure (eTable 5 in Supplement 1). 43cond, the independence assumption requires that there are no unmeasured confounders of the SNVs and outcome.Third, the exclusion restriction assumption states that the only effect of the SNVs on the outcome operates through the exposure.Fourth, we must assume monotonicity, meaning that our defined GRS does not have opposite effects on individuals within the sample. 44 first modeled the association of 2 cataracts-GRS and myopia-GRS with all-cause dementia using logistic regressions.To evaluate potential reverse causation, we additionally modeled the association between AD-GRS and Statistical tests were performed with an α = .05and were 2-tailed and unpaired.

Results
We

Mendelian Randomization
Genetic risk for cataracts (primary cataracts-GRS) was not associated with all-cause dementia (OR,  Using MR on our primary cataract-GRS, estimates for the possible causal association of cataracts with dementia were all greater than 1 (estimates ranging from 1.21 to 1.37) (Table 3), although no estimates were statistically significant.There was no evidence of horizontal pleiotropy, using the MR-Egger method (β = −0.01;P = .59).Similar estimates were noted with MR-PRESSO analysis (OR, 1.21; 95% CI, 0.98-1.50;global test for horizontal pleiotropy; P = .37). 45The association between individual cataract SNVs and all-cause dementia is shown in eFigure 1 in Supplement 1, with no evidence for large outliers.Mendelian randomization indicated greater odds of VaD with cataract (inverse variance weighted (OR, 1.92; 95% CI, 1.26-2.92,with all MR estimates ranging from 1.92 to 2.33) (Table 3), and all estimates were statistically significant except for MR-Egger (OR, 2.33; 95% CI, 0.90-6.02),which also provided no evidence of horizontal pleiotropy (intercept = −0.01;P = .66)(eFigure 2 in Supplement 1).

Discussion
We evaluated vision impairments and dementia risk in UKB, using observational and MR approaches.
Cataracts and poor visual acuity were associated with dementia risk.Higher genetic risk for cataracts was associated with increased risk of VaD.Analysis using 2-sample MR estimators showed cataracts increased VaD risk 2-fold.Genetic risk for AD was not associated with cataracts, suggesting observational associations are not due to reverse causation.We found evidence that cataracts may be associated with brain atrophy, specifically in global gray matter.In addition, myopia was associated with a decreased risk of dementia, but we found no evidence to support causality.
Together, these results are consistent with the hypothesis that cataracts increase the risk of dementia.Models for cataracts include adjustment for age at visit, self-reported sex, selfreported racial and ethnic identity, index of multiple deprivation by country of origin, binary indicators for history of comorbidities (falls, broken bones, cardiovascular disease, stroke, diabetes, and problems hearing), and imaging center.Models for cataracts-GRS (primary) include adjustment for age, sex, first 10 principal components, imaging center, and intracranial volume.Error bars indicate 95% CI.
Our results extend current evidence by observing that the association between cataracts and dementia may be causal and that cataracts are associated with brain volumes.Observational studies have found that cataracts were associated with increased dementia risk. 4,5,46,47Some previous work found no association between cataracts and dementia, 48,49 but was underpowered.One MR study did not find a strong link between cataracts and AD 22 but did not examine other dementia outcomes, such as VaD.
Our findings are strengthened by evaluating multiple ADRD-related outcomes, including neuroimaging markers.Few prior studies have examined associations between vision and ADRDrelated neurodegeneration. 36,37,50In our study, cataracts were associated with increased brain atrophy, but we did not find evidence for AD-related neurodegeneration.Because a history of cataracts was associated with VaD and white matter hyperintensity volumes (a marker of smallvessel ischemic disease), 51 there may be vascular mechanisms linking cataracts and dementia.
Additionally, our observational work suggested an association between diabetic retinopathy and dementia.Future studies will need to confirm underlying mechanisms and should investigate other eye diseases (observationally and in MR studies), including diabetic retinopathy, optic neuropathy, and other vascular causes of eye disease. 52[55] Our results are largely consistent with previous literature showing that poor visual acuity [6][7][8] is associated with increased dementia risk.However, visual acuity was not associated with any neuroimaging measures, in contrast to another study. 36Myopia was associated with a decreased risk of dementia in observational models.Although this is consistent with some prior work, 56 the finding is likely due to confounding, as the myopia-GRS was not associated with dementia.
The validity of our MR analyses depends on 4 assumptions. 20,21,43First, we confirmed that genetic instruments estimate each exposure of interest.Second, while we cannot prove that the independence assumption is met, we have adjusted for the strongest potential confounder: principal components. 57Third, we also believe the exclusion restriction assumption holds in our MR models, as there was no evidence for horizontal pleiotropy.Fourth, the monotonicity assumption limits the generalizability of our estimates and may not represent the true effect of cataracts on dementia in different populations.

Strengths and Limitations
Our study has important strengths compared with prior work, including the strength of causal inference, a large sample, and an investigation into biological pathways.
This study has some important limitations.First, MR analyses are underpowered, which is reflected in the wide CIs of our MR estimates.However, by also including observational methods and multiple GRS, this study suggests there is a causal effect of cataracts on dementia by triangulation. 58cond, the genetic analyses were restricted to individuals with European ancestry, meaning genetic results may not be generalizable to other genetic backgrounds.Third, the present results do not consider monocular vs binocular presentation of cataracts, potential delays in cataract surgery by dementia status, or other factors.Fourth, the individuals in the UKB are relatively young (mean age, 62 years) and healthy, 59 leading to only a smaller number of cases of ADRD.This study should be replicated in an older cohort with more diverse representation.

Conclusions
In this cohort and bidirectional MR study of UKB participants, we added important insights into the link between eye conditions, visual impairment, and dementia risk by combining both observational and MR analyses.We found that cataracts, but not myopia, may increase the risk of dementia,

Figure 2 .
Figure 2. Association Between Cataracts or Cataracts-Genetic Risk Scores (GRS) and Total Brain and Gray Matter Volumes Eye Conditions and Risk of Neurodegeneration and DementiaWe included participants aged 55 years or older in this analysis (age 55-70 years at baseline).We excluded individuals with dementia at baseline or without self-reported visual history.Analyses using genetic risk score (GRS) or MR were further restricted to those with European genetic ancestry due to concerns that variants may not generalize to those with non-European ancestry.

Table 2 .
Cox Proportional Hazards Regression Models for the Associations Between Eye Conditions and All-Cause Dementia, AD, and VaD a Abbreviations: AD, Alzheimer disease; HR, hazard ratio; VaD, vascular dementia.aModelsinclude adjustment for age at visit, self-reported sex, self-reported racial and ethnic identity, index of multiple deprivation by country of origin, and binary indicators for history of falls, broken bones, cardiovascular disease, stroke, diabetes, and problems hearing.bAdditionally adjusted for use of corrective lenses.

Table 3 .
MR Estimates for Vision Impairment and Dementia a a Models adjusted for age, sex, and first 10 principal components to proxy for genetic ancestry.
VaD. Mendelian randomization and imaging findings suggested that non-AD biological pathways may explain this association.This study lends further support for the hypothesis that treatment or prevention of cataracts may prevent dementia.Clinical screening and treatment of cataracts may be important clinical strategies to improve quality of life.Future studies should test whether vision screening or cataract surgery in those with co-occurring dementia risk factors are effective at reducing the risk of dementia.Chatziralli IP, Kazantzis D, Chatzirallis AP, et al.Cardiometabolic factors and risk of non-arteritic anterior ischemic optic neuropathy: a systematic review and meta-analysis.Graefes Arch Clin Exp Ophthalmol.2022;260 (5):1445-1456.doi:10.1007/s00417-021-05522-453.Wang L, Benzinger TL, Su Y, et al.Evaluation of tau imaging in staging Alzheimer disease and revealing interactions between β-amyloid and tauopathy.JAMA Neurol.2016;73(9):1070-1077. doi:10.1001/jamaneurol.2016.207854.Moore EE, Gifford KA, Khan OA, et al.Cerebrospinal fluid biomarkers of neurodegeneration, synaptic dysfunction, and axonal injury relate to atrophy in structural brain regions specific to Alzheimer's disease.Spierer O, Fischer N, Barak A, Belkin M. Correlation between vision and cognitive function in the elderly: a cross-sectional study.Medicine (Baltimore).2016;95(3):e2423.doi:10.1097/MD.000000000000242357.Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians.BMJ.2018;362:k601.doi:10.1136/bmj.k60158.Lawlor DA, Tilling K, Davey Smith G. Triangulation in aetiological epidemiology.Int J Epidemiol.2016;45(6): 1866-1886.59.Fry A, Littlejohns TJ, Sudlow C, et al.Comparison of sociodemographic and health-related characteristics of UK Biobank participants with those of the general population.Am J Epidemiol.2017;186(9):1026-1034.doi:10.1093/aje/kwx246 60.Besagar S, Yonekawa Y, Sridhar J, et al.Association of socioeconomic, demographic, and health care access disparities with severe visual impairment in the US.JAMA Ophthalmol.2022;140(12):1219-1226. doi:10.1001/jamaophthalmol.2022.456661.Balls-Berry JJE, Babulal GM.Health disparities in dementia.Continuum (Minneap Minn).2022;28(3):872-884.International Classification of Diseases (ICD) Codes Used to Extract Additional AD and ADRD diagnoses From Primary Care and In-Patient Electronic Health Records Through 2021 eTable 2. SNPs and Their Log OR Effect Estimates Included in the Primary Cataracts-GRS eTable 3. SNPs and Their Log OR Effect Estimates Included in the Primary Myopia-GRS eTable 4. SNPs and Their Log OR Effect Estimates Included in the AD-GRS eTable 5. Associations Between Genetic Risk Scores (Cataracts-GRS, Myopia-GRS, and AD-GRS) With Their Respective Outcomes in UK Biobank eTable 6. Cox Models for the Associations Between Glaucoma, AMD, and Diabetic Retinopathy With All-Cause Dementia, AD, and VaD eTable 7. Association Between Cataracts or Cataracts-GRS and Brain Regions (mm 3 ) Associated With Dementia or Vision eTable 8. Association Between Primary GRS (Obtained From the 23andMe Replication Study) for Cataracts or Myopia, and Incident Dementia, AD, and VaD Among Participants Older Than 60 at Baseline eTable 9. Association Between Secondary GRS (Obtained From GERA Cohort) and Incident Dementia, AD, and VaD Among Participants Older Than 60 at Baseline eTable 10.Associations Between AD-GRS, With and Without APOE, and Vision Outcomes eTable 11.Summary Reverse Causation MR Estimates for: 1) the Association Between AD and Self-Reported and ICD Diagnoses of Cataracts, 2) the Association Between AD and Myopia, and 3) the Association Between AD and Binary 20/40 Vision eFigure 1. Association Between 43 Cataracts SNPs and Both Cataracts and Dementia eFigure 2. Association Between 43 Cataracts SNPs and Both Cataracts and Vascular Dementia eFigure 3. Association Between 27 AD SNPs and Both Cataracts and Dementia 52. doi:10.1212/CON.0000000000001088SUPPLEMENT 1. eTable 1.